Type 2 diabetes mellitus is a common chronic disease that develops in most populations late in middle age. The Pima Indians of Arizona have a very high prevalence of this disease and, in contrast to many populations, the disease often presents at an earlier age. As a result of the long-term epidemiologic studies, the familial nature of the disease is well-documented, and segregation analysis suggests that genetic determinants may influence age of onset. Genetic determinants of type 2 diabetes mellitus and its risk factors are being sought using techniques of genetic linkage analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies. An autosomal genome-wide linkage study, using 516 genetic markers, has been completed for 1338 individuals in 112 pedigrees potentially informative for linkage studies of diabetes. The results of these analyses identified strong evidence for a locus influencing both obesity and diabetes on chromosome 11q. Evidence for an additional locus influencing diabetes and insulin secretory function was found on chromosome 1q. Efforts to identify the causative polymorphism or polymorphisms in both of these regions are currently underway using both a systematic analysis of linkage disequilibrium and analyses of candidate genes. Methods for statistical analyses of these studies are also being evaluated. In addition, techniques to assess parent-of-origin effects in linkage analysis have been developed and these are being applied to the genome-wide linkage study. These analyses have identified several genomic regions with tentative evidence for loci with parent-of-origin effects influencing diabetes and obesity and strong evidence for a paternally-expressed birth weight locus on chromosome 11p.